leep results from the complex interaction of multiple neurotransmitter systems and the influences of sleep regulatory systems with other mechanisms (e.g., those which control temperature, respiration, and blood pressure). Thus, the observation of a drug's effect on sleep is relatively straightforward, but the interpretation of the mechanisms of its actions is very difficult.
A drug-induced increase in sleep, for instance, might result from a "direct" effect on sleep mechanisms, or alternatively might result from a reduction in processes which are incompatible with sleep (e.g., anxiety or pain), or it might alter other systems that affect sleep (e.g., temperature or circadian processes). Moreover, many of the pharmacologic probes thought to have a specific effect on one neurotransmitter system may influence others as well. Clonidine, for instance, an alpha-2 noradrenergic agonist, has been reported to alter serotonin function as well. A drug's acute actions may also differ from when it is administered chronically. Thus, interpretations of the mechanism by which drugs influence sleep must be made with caution.Hypnotics. By definition, these agents enhance total sleep and reduce sleep latency. The most widely used hypnotics, the benzodiazepines, act by binding to high affinity, stereospecific binding sites which are part of the benzodiazepine receptor complex. This structure also includes a GABA recognition site and a chloride ionophore; it is thought that benzodiazepine and GABA agonists ultimately enhance chloride ion flow, resulting in hyperpolarization and decreased cell firing. Barbiturate hypnotics bind at or near the chloride ionophore, and ethanol alters the function of this site. Benzodiazepines have potent slow-wave (Stage 3 and 4) sleep suppressing properties, but only mildly decrease REM sleep (Figure 1). Barbiturates and ethanol have relatively little effect or may increase NREM sleep, but potently decrease REM sleep. Ethanol may also produce increased arousals throughout the night, possibly by a withdrawal phenomenon due to its rapid metabolism. Non-prescription ("over-the-counter") hypnotics are usually antihistamines, which may have some sleep-enhancing properties. Many have significant anticholinergic properties, which limits their usefulness, particularly in the elderly.
Effect of a benzodiazepine (flunitrazepam [2 mg]) on sleep in a normal subject. Flunitrazepam shortens sleep onset and delays the appearance of REM sleep. Stage 4 sleep is increased early in the night but is reduced during the latter part.Compounds altering purinergic function. The purines inosine and hypoxanthine may interact with the benzodiazepine receptor. There is evidence that inosine may be involved in anxiety-related behaviors. Some drugs which enhance adenosinergic activity produce behavioral sedation, and may enhance sleep. The adenosine antagonist caffeine reduces sleep, and may reduce REM, particularly in the later part of the night (Figure 2). Benzodiazepines may decrease adenosine uptake; however, animals fed a caffeine-rich diet have increased adenosine receptors without alterations in benzodiazepine receptors.
Stimulants. Dextroamphetamine and pemoline (Figure 3), which enhance catecholamine and dopaminergic activity, increase sleep latency, decrease total sleep time, and greatly reduce REM sleep. The REM sleep reduction effect is due to increased wakefulness, in contrast to drugs which primarily alter noradrenergic or serotonergic activity, in which REM sleep reduction occurs regardless of changes in total sleep or wakefulness. Wakefulness can also be increased by the beta-carbolines, which bind to the benzodiazepine recognition site but which have opposite effects, and hence are considered "inverse agonists."
Antidepressants. Tricyclic antidepressants, which block the reuptake of synaptic norepinephrine or serotonin, vary in their potency as sedatives. Acute effects on NREM sleep in depressed patients include reports of increases, decreases, or no effect. Monoamine oxidase inhibitors, some of which pharmacologically resemble stimulants, may have disrupting effects on sleep. With the exception of some very new, experimental agents, all common antidepressants are potent REM suppressants. Some authors have speculated that this action plays an important part in their therapeutic effects.
Compounds relatively specific to biogenic amines. As a generalization, in human studies, drugs which enhance noradrenergic activity decrease REM sleep, while those that decrease noradrenergic function enhance REM sleep. An example of the latter is alpha-methyl-paratyrosine, which blocks the synthesis of norepinephrine, and may enhance REM sleep in normal humans, with relatively little effect on total sleep. In contrast, drugs which decrease serotonergic activity may decrease REM sleep. Parachlorophenylalanine (PCPA), which reduces the synthesis of serotonin, causes profound reductions in REM sleep. With time, sleep may return toward normal, although serotonergic function remains reduced; this observation emphasizes the importance of distinguishing between acute and chronic drug effects. One major discrepancy between human and animal studies which has never been satisfactorily resolved is that in animals, in contrast to humans, drugs which decrease serotonergic function may also have profound effects on total sleep. This difference may be explained by the higher doses of drugs used in animal work, that the crucial element is the rate of change (rather than absolute amounts) of biogenic amine activity or that serotonin may act as a releasing mechanism for other substances which affect sleep.
Cholinergic agents. Drugs which enhance muscarinic cholinergic function may increase REM sleep, while blockers such as scopalamine decrease it. In normal volunteers, intravenous infusion of the acetylcholine catabolism blocker physostigmine or the receptor agonist arecoline may induce REM periods. Patients with depression may have increased sensitivity to this process, which has been taken as evidence that one aspect of depression involves cholinergic overactivity. In cats, administration of the metabolism blocker neostigmine into the pontine reticular formation induces REM-like states, while injection into the medullary or midbrain reticular formation suppresses REM.
Circulating sleep factors. A number of endogenous compounds which enhance sleep have been detected in the blood and CSF. These include delta-sleep inducing peptide, arginine vasotocin, the adrenal steroid tetrahydrodeoxycorticosterone, cholecystokinin, and muramyl dipeptide. The lymphokines interleukin 1 and 2 may increase human sleep. These latter observations suggest the importance of further studies of the possible interaction of the immune system with sleep.
In summary, pharmacologic agents may provide useful information on the regulation of sleep, and conversely the observed effects on sleep may contribute to the understanding of a drug's mechanisms of action. As noted above, drugs often affect multiple neurotransmitters, and they may influence sleep indirectly by altering other systems. Pharmacologic studies, therefore, should be used in conjunction with other approaches in reaching conclusions about a sleep-inducing drug's mechanisms of action and the processes by which such drugs transform an individual from one, who is awake and aware of being awake or even very sleepy, to one, who without knowing it, is asleep.
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